CD5 chimeric antigen receptor for adoptive T cell therapy

a t cell and chimeric antigen technology, applied in the field of immunology, cell biology, molecular biology, medicine, can solve the problems of high risk of incurable relapse, low cure rate of adult t-all cases, and difficulty in using car t cells against t-cell malignancies, so as to improve t cell persistence and antitumor responses.

Active Publication Date: 2020-09-29
BAYLOR COLLEGE OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In particular embodiments, one can modify the CD5 CAR, such as to eliminate cellular FcγR interactions to improve T cell persistence and antitumor responses.

Problems solved by technology

Cure rates for adult T-ALL cases are low (20-40%) and there is a high risk of incurable relapse.
However, using CAR T cells against T-cell malignancies is frequently challenging because of shared expression of most surface antigens between normal and malignant T cells, which would lead to T-cell fratricide.
Currently, there are no adoptive cell therapy options for T-cell leukemia.

Method used

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  • CD5 chimeric antigen receptor for adoptive T cell therapy
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  • CD5 chimeric antigen receptor for adoptive T cell therapy

Examples

Experimental program
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Effect test

example 1

CD5 CAR for T-Cell Malignancies

[0183]Chimeric antigen receptors (CARs) have emerged as a powerful therapeutic tool redirecting patient's own T cells to treat hematologic malignancies—in particular, those of B cell origin. However, T cell malignancies remain a more challenging task for CAR T cells owing to the shared expression of targetable tumor-associated antigens, e.g., CD5, between normal and cancerous T cells, potentially invoking fratricide of CAR T cells.

[0184]The present disclosure provides a novel CAR targeting CD5, a common marker expressed in most T-cell leukemia / lymphoma blasts and normal T cells. As described below, upon transduction with a CD5 CAR, T cells displayed limited and transient fratricide and eventually acquired resistance to self-killing. Expansion of CD5 CAR T cells coincided with downregulation of CD5 from the cell surface. At the same time, CD5 CAR T cells efficiently recognized and completely eliminated CD5-positive T-ALL and T cell lymphoma cell lines i...

example 2

A T Cell-Directed Chimeric Antigen Receptor for the Selective Treatment of T Cell Malignancies

[0185]Lymphoid malignancies produce significant morbidity and mortality in pediatric and adult patients (Dores, et al., 2012). Although recent advances in chemotherapy have improved disease-free survival, prognosis remains poor for primary chemotherapy-refractory or relapsed patients, and all patients may have significant short-term and long-term toxicities from their treatment (Kantarjian, et al., 2010; Gökbuget, et al., 2012; DeAngelo, et al., 2007; Goldberg, et al., 2003; Oudot, et al., 2008; O'Brien, et al., 2008). Recent studies in patients with B lymphoid malignancies have demonstrated the remarkable potency of chimeric antigen receptors (CARs) that can redirect T cells to the CD19 antigen present on normal and malignant B cells with complete response rates of >90% even in patients with refractory or relapsed disease (Brentjens, et al., 2013; Maude, et al., 2014). Such response rates,...

example 3

Modifications of CD5 Chimeric Antigen Receptors

[0232]In particular embodiments, a CD5 CAR has modifications to one or more components of the polynucleotide encoding the CAR and / or the immune cell harboring the polynucleotide. In certain embodiments, a particular anti-CD5 scFv is utilized, including those that are not specifically listed elsewhere herein. For the intracellular signaling domains, any suitable combination may be employed, and the skilled artisan knows how to test the efficacy and safety of the combinations based on routine practices described elsewhere herein.

[0233]One CAR component that may be varied depending on the particular CD5 CAR is the spacer and / or hinge region. A spacer region links the antigen binding domain to the transmembrane domain. In specific embodiments the spacer is flexible enough to allow the antigen binding domain to orient in different directions to facilitate antigen recognition. In certain embodiments, the hinge region is from IgG1. In specific...

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Abstract

Embodiments of the disclosure include methods and compositions related to immunotherapy that targets CD5. In particular embodiments, immune cells engineered to comprise a chimeric antigen receptor (CAR) that targets CD5 are contemplated, and uses thereof. In particular embodiments, the immune cells expressing the CAR do not commit fratricide to any great extent against T cells that express CD5 and which are endogenous to an individual receiving the immune cells.

Description

[0001]This application is a national phase application under 35 U.S.C. § 371 that claims priority to International Application No. PCT / US16 / 29014 filed Apr. 22, 2016 which claims priority to U.S. Provisional Patent Application Ser. No. 62 / 151,609, filed Apr. 23, 2015, all of which are incorporated by reference herein in their entirety.INCORPORATION OF SEQUENCE LISTING[0002]The instant application contains a Sequence Listing, named “Sequence_Listing.txt” (14,300 bytes), created Oct. 23, 2017, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.TECHNICAL FIELD[0003]The present disclosure concerns at least the fields of immunology, cell biology, molecular biology, and medicine, including cancer medicine.BACKGROUND[0004]Acute Lymphoblastic Leukemia (ALL) is the most common cancer in pediatric patients. T-lineage Acute Lymphoblastic Leukemia (T-ALL) accounts for 15% of ALL cases in children and 20-25% in adults. Cure rates for a...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K38/17C07K16/30C07K14/715A61K39/395A61P35/02A61K35/17C07K16/28C12N5/0783C07K14/705C07K14/725A61K45/06
CPCA61K39/395A61P35/02A61K45/06A61K38/1774A61K35/17C12N5/0636C07K14/70521C07K14/715C07K16/2896C07K14/7051C07K16/30C07K2319/03C07K2317/92C07K2317/622C07K2317/94
Inventor MAMONKIN, MAKSIMBRENNER, MALCOLM K.
Owner BAYLOR COLLEGE OF MEDICINE
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